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Abstract: The brain is a complex information processing system, which can be divided into sub-systems, such as the sensory organs, functional areas in the cortex, and motor control systems. In this sense, most of the mathematical models developed in the field of neuroscience have mainly targeted a specific sub-system. In order to understand the details of the brain as a whole, such sub-system models need to be integrated toward the development of a neurophysiologically plausible large-scale system model. In the present work, we propose a model integration library where models can be connected by means of a common data format. Here, the common data format should be portable so that models written in any programming language, computer architecture, and operating system can be connected. Moreover, the library should be simple so that models can be adapted to use the common data format without requiring any detailed knowledge on its use. Using this library, we have successfully connected existing models reproducing certain features of the visual system, toward the development of a large-scale visual system model. This library will enable users to reuse and integrate existing and newly developed models toward the development and simulation of a large-scale brain system model. The resulting model can also be executed on high performance computers using Message Passing Interface (MPI). [Copyright &y& Elsevier]

Background: Low-grade systemic inflammation may be a key player in the immune activation that has been reported for mental health deterioration. We hypothesised that elevated serum levels of inflammatory cytokines increase neuroinflammation and exacerbate depressive symptoms. Methods: The participants were part of a cohort study for whom data was available for both 2015 and 2019. In 2015, blood samples were collected from 232 participants. Their depressive symptoms were assessed both 2015 and 2019 using the Centre for Epidemiologic Studies Depression Scale (CES-D) (n = 33). The multiplex immunoassay system (Luminex® 200) was used to measure the serum concentrations of IL-6, IL-10, IL-12, IL-17A and TNFα. Data were analysed using linear models with the level of significance considered to be p < 0.05. Results: After controlling for age, BMI, smoking and alcohol consumption, in 2015 the serum concentrations of IL-17A and TNFα in 2015 were significantly positively associated with the CES-D scores of women (standardised β (B) =.027, p < 0.01 and B = 0.26, p < 0.01, respectively). The serum concentrations of IL-17A and TNFα of men were significantly positively associated with the CES-D scores of 2019 (B = 0.62, p = 0.02 and B = 0.59, p = 0.02, respectively). Conclusions: In this cross-sectional study, we found a significant positive correlation between the depressive symptoms and serum TNFα and IL-17A levels of women. In addition, our longitudinal findings suggest the possibility that TNFα and IL-17A could elevate the depressive symptoms of men. [ABSTRACT FROM AUTHOR]

To investigate if the pretreatment dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-based radiomics machine learning predicts the pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer patients. Seventy-eight breast cancer patients who underwent DCE-MRI before NAC and confirmed as pCR or non-pCR were enrolled. Early enhancement mapping images of pretreatment DCE-MRI were created using subtraction formula as follows: Early enhancement mapping = (Signal 1 min – Signal pre)/Signal pre. Images of the whole tumors were manually segmented and radiomics features extracted. Five prediction models were built using five scenarios that included clinical information, subjective radiological findings, first order texture features, second order texture features, and their combinations. In texture analysis workflow, the corresponding variables were identified by mutual information for feature selection and random forest was used for model prediction. In five models, the area under the receiver operating characteristic curves (AUC) to predict the pCR and several metrics for model evaluation were analyzed. The best diagnostic performance based on F-score was achieved when both first and second order texture features with clinical information and subjective radiological findings were used (AUC = 0.77). The second best diagnostic performance was achieved with an AUC of 0.76 for first order texture features followed by an AUC of 0.76 for first and second order texture features. Pretreatment DCE-MRI can improve the prediction of pCR in breast cancer patients when all texture features with clinical information and subjective radiological findings are input to build the prediction model. [ABSTRACT FROM AUTHOR]

Social behavior is essential for health, survival, and reproduction of animals; however, the role of astrocytes in social behavior remains largely unknown. The transmembrane protein CD38, which acts both as a receptor and ADP‐ribosyl cyclase to produce cyclic ADP–ribose (cADPR) regulates social behaviors by promoting oxytocin release from hypothalamic neurons. CD38 is also abundantly expressed in astrocytes in the postnatal brain and is important for astroglial development. Here, we demonstrate that the astroglial‐expressed CD38 plays an important role in social behavior during development. Selective deletion of CD38 in postnatal astrocytes, but not in adult astrocytes, impairs social memory without any other behavioral abnormalities. Morphological analysis shows that depletion of astroglial CD38 in the postnatal brain interferes with synapse formation in the medial prefrontal cortex (mPFC) and hippocampus. Moreover, astroglial CD38 expression promotes synaptogenesis of excitatory neurons by increasing the level of extracellular SPARCL1 (also known as Hevin), a synaptogenic protein. The release of SPARCL1 from astrocytes is regulated by CD38/cADPR/calcium signaling. These data demonstrate a novel developmental role of astrocytes in neural circuit formation and regulation of social behavior in adults. Synopsis: Postnatal expression of the ADP‐ribosyl cyclase CD38 in astrocytes regulates neuronal circuit formation and social behavior in adults.Postnatal expression, but not adult expression, of CD38 in astrocytes regulates social memory.Astrocytic CD38 promotes excitatory synapse formation in the medial prefrontal cortex and hippocampal CA1 and CA2.Astrocytic CD38 promotes secretion of the synaptogenic protein SPARCL1 via cyclic ADP–ribose and calcium signaling. [ABSTRACT FROM AUTHOR]

An abstract of the research paper "Generating Realistic Retinal Image for Whole Visual System Modeling," by Takayuki Kannon and Shiro Usui, presented at the Twentieth Annual Computational Neuroscience Meeting, held in Stockholm, Sweden, from July 23-28, 2011.

Although depression and body weight have individually been associated with chronic pain (CP), it currently remains unclear whether the combination of depressive symptoms (DS) and being underweight/overweight is related to CP. Therefore, we herein investigated the relationships among depression, body mass index (BMI), and CP in community-dwelling middle-aged and elderly individuals. Participants comprised 2216 inhabitants of Shika town in Ishikawa prefecture, Japan, including 1003 males (mean age of 68.72 years, standard deviation (SD) of 8.36) and 1213 females (mean age of 69.65 years, SD of 9.36). CP and DS were assessed using a CP questionnaire and Geriatric Depression Scale-15, respectively. The Breslow–Day test indicated that DS positively correlated with lumbar/knee pain in the BMI < 25 group, but not in the BMI ≥ 25 group. Furthermore, lumber/knee pain was related to a higher BMI. These results were confirmed by a logistic analysis with age, sex, BMI, solitary living, the duration of education, no exercise/hobbies, smoking history, alcohol intake, and medical treatment for diabetes, hyperlipidemia, or hypertension as confounding factors. The present study indicates the importance of considering DS and BMI in the prevention of CP. Further studies are needed to clarify the causal relationships among depression, BMI, and CP. [ABSTRACT FROM AUTHOR]

Dopamine signaling in the brain is a complex phenomenon that strongly contributes to emotional behaviors. Medium spiny neurons (MSNs) play a major role in dopamine signaling through dopamine D1 receptors (D1Rs) or dopamine D2 receptors (D2Rs) in the striatum. cAMP/protein kinase A (PKA) regulates phosphorylation signals downstream of D1Rs, which affects the excitability of MSNs, leading to reward-associated emotional expression and memory formation. A combination of phosphoproteomic approaches and the curated KANPHOS database can be used to elucidate the physiological and pathophysiological functions of dopamine signaling and other monoamines. Emerging evidence from these techniques suggests that the Rap1 pathway plays a crucial role in the excitability of MSNs, leading to the expression of emotional behaviors. [ABSTRACT FROM AUTHOR]

Although the relationship between hypertension and depression is influenced by several physiological factors, including body weight and other lifestyle factors, such as eating behavior, the specific involvement of depression in hypertension remains unclear. Therefore, this epidemiological study examined the role of body weight in the relationship between hypertension and depressive symptoms among the middle-aged and elderly living in the community of Shika town. In total, 1141 males and 1142 females with mean ages of 69.09 and 70.61 years, respectively, participated this study. Physiological factors, including blood pressure, body mass index (BMI), and lifestyle, were investigated in a medical check-up in Shika town. Depressive symptoms were evaluated using the Geriatric Depression Scale 15 (GDS-15). A two-way analysis of covariance exhibited a significant interaction between the two hypertensive groups and body size groups on GDS in females. The post hoc Bonferroni method showed that in the hypertensive groups, GDS was significantly higher in the underweight group (BMI < 18.5) than in the standard/overweight group; however, this relationship was not observed in the no-hypertensive groups. Multiple regression analysis also verified this relationship. Therefore, it is suggested that the combination of hypertension and being underweight is associated with depressive symptoms only in females. [ABSTRACT FROM AUTHOR]

We describe a postmortem case of familial idiopathic basal ganglia calcification (FIBGC) in a 72‐year‐old Japanese man. The patient showed progressive cognitive impairment with a seven‐year clinical course and calcification of the basal ganglia, thalami, and cerebellar dentate nuclei. A novel heterozygous missense variant in SLC20A2 (c.920C>T/p.P307L), a type III sodium‐dependent phosphate transporter (PiT‐2), was subsequently identified, in addition to typical neuropathological findings of FIBGC, such as capillary calcification of the occipital gray matter, confluent calcification of the basal ganglia and cerebellar white matter, widespread occurrence of vasculopathic changes, cerebrovascular lesions, and vascular smooth muscle cell depletion. Immunohistochemistry for PiT‐2 protein revealed no apparent staining in endothelial cells in the basal ganglia and insular cortex; however, the immunoreactivity in endothelial cells of the cerebellum was preserved. Moreover, Western blot analysis identified preserved PiT‐2 immunoreactivity signals in the frontal cortex and cerebellum. The variant identified in the present patient could be associated with development of FIBGC and is known to be located at the large intracytoplasmic part of the PiT‐2 protein, which has potential phosphorylation sites with importance in the regulation of inorganic phosphate transport activity. The present case is an important example to prove that FIGBC could stem from a missense variant in the large intracytoplasmic loop of the PiT‐2 protein. Abnormal clearance of inorganic phosphate in the brain could be related to the development of vascular smooth muscle damage, the formation of cerebrovascular lesions, and subsequent brain calcification in patients with FIBGC with SLC20A2 variants. [ABSTRACT FROM AUTHOR]

Apolipoprotein E E4 (APOE4) is a risk factor for cognitive decline. A high blood vitamin C (VC) level reduces APOE4-associated risk of developing cognitive decline in women. In the present study, we aimed to examine the effects of functional variants of VC transporter genes expressed in the brain (SLC2A1, SLC2A3, and SLC23A2) on APOE4-associated risk of developing cognitive decline. This case–control study involved 393 Japanese subjects: 252 cognitively normal and 141 cognitively impaired individuals (87 mild cognitive impairment and 54 dementia). Database searches revealed that rs1279683 of SLC23A2, and rs710218 and rs841851 of SLC2A1 are functional variants that are significantly associated with the altered expression of the respective genes and genotyped as three single nucleotide variants (SNVs). When stratified by SNV genotype, we found a significant association between APOE4 and cognitive decline in minor allele carriers of rs1279683 (odds ratio [OR] 2.02, 95% CI, 1.05–3.87, p = 0.035) but not in the homozygote carriers of the major allele. Significant associations between APOE4 and cognitive decline were also observed in participants with major allele homozygotes of rs710218 (OR 2.35, 95% CI, 1.05–5.23, p = 0.037) and rs841851 (OR 3.2, 95% CI, 1.58–6.46, p = 0.0012), but not in minor allele carriers of the respective SNVs. In contrast, the three functional SNVs showed no significant effect on cognitive decline. Our results imply that functional SNVs of VC transporter genes can affect APOE4-associated risk of developing cognitive decline via altered VC levels in the brain. [ABSTRACT FROM AUTHOR]

A polymorphism in the ADRB3 gene (Trp64Arg) has been associated with obesity, insulin resistance, and hypertension. This cross-sectional study investigated the relationships among this polymorphism, hypertension, and insulin resistance values (HOMA-IR) in 719 Japanese subjects aged 40 years and older. The genotype frequencies of Trp64Trp (homozygous, wild), Trp64Arg (heterozygous, variant), and Arg64Arg (homozygous, variant) were 466 (65%), 233 (32%), and 20 (3%), respectively. Insulin resistance was associated with an increased risk of hypertension in a Japanese population. This relationship was dependent on the presence or absence of the Trp64Arg polymorphism (odds ratio, 2.054; confidence interval, 1.191 to 3.541; P value, 0.010). Therefore, the Trp64Arg polymorphism of ADRB3 was associated with hypertension and insulin resistance in a healthy Japanese population. This relationship, which was dependent on the polymorphism, may predict the development of hypertension and diabetes. [ABSTRACT FROM AUTHOR]

While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its paralogue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca2+-binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b−/− mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b−/− neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b−/− and Calr+/− mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca2+ homeostasis. [ABSTRACT FROM AUTHOR]

Aims/Introduction: A low insulin secretion capacity has been implicated in the high prevalence of non‐obese diabetes in East Asians. As alcohol consumption alters insulin and glucose metabolism, we tested the hypothesis that alcohol consumption contributes to impaired insulin secretion and glucose intolerance in lean/normal‐weight non‐diabetic Japanese men. Materials and Methods: This cross‐sectional study was undertaken among the residents of Shika town, Japan, between 2011 and 2017. A total of 402 non‐diabetic men, including participants with normal fasting plasma glucose (FPG) and impaired FPG (FPG 5.6–6.9 mmol/L), and aged ≥40 years, were examined. FPG, the homeostasis model assessment of insulin secretion capacity (HOMA‐B) and alcohol consumption were evaluated and compared between the body mass index (BMI) <25 and BMI ≥25 groups. Results: HOMA‐B levels were lower in the BMI <25 group than in the BMI ≥25 group. Alcohol consumption correlated with a low HOMA‐B level regardless of BMI, and, thus, the HOMA‐B levels of alcohol drinkers were significantly lower in the BMI <25 group. A multivariable logistic regression analysis showed that alcohol consumption, even light‐to‐moderate consumption (1–25 g/day), was associated with significantly low levels of HOMA‐B and impaired FPG in the BMI <25 group. Among participants with impaired FPG, a low level of HOMA‐B was observed in alcohol drinkers, but not in non‐drinkers. In contrast, light‐to‐moderate alcohol consumption was not related to HOMA‐B or FPG in the BMI ≥25‐group. Conclusion: Alcohol consumption, even a small amount, might contribute to reductions in HOMA‐B levels and impaired FPG in lean/normal‐weight Japanese men. [ABSTRACT FROM AUTHOR]

Study objectives: Although associations between sleep quality and environmental factors and nutrient intake have been reported, interactions between these factors have not been elucidated in detail. Therefore, this cross-sectional study examined the effects of regular exercise and nutrient intake on sleep quality using the Pittsburgh Sleep Quality Index (PSQI), which is the most frequently used index for sleep evaluation. Methods: The participants included 378 individuals aged 40 years or older living in Shika Town, Ishikawa Prefecture. Of these individuals, 185 met the inclusion criteria. The participants completed a self-administered questionnaire assessing lifestyle habits and frequency and duration of exercise, the PSQI, and the brief-type self-administered diet history questionnaire (BDHQ) on nutrient intake. Results: A two-way analysis of covariance on regular exercise and PSQI scores indicated that protein intake (17.13% of energy) was significantly higher in the regular exercise and PSQI ≤10 groups than in the non-regular exercise or PSQI ≥11 groups (p = 0.002). In a multiple logistic regression analysis with PSQI scores (≤10 and ≥11), protein intake was a significant independent variable in any of the models adjusted for confounding factors such as age, sex, body mass index, current smoker, and current drinker (OR: 1.357, 95% CI: 1.081, 1.704, p = 0.009) in the regular exercise group but not in the non-regular exercise group.Conclusions We identified a positive relationship between sleep quality and protein intake in the regular exercise group. These findings suggest that regular exercise at least twice a week for 30 minutes or longer combined with high protein intake contributes to good sleep quality. [ABSTRACT FROM AUTHOR]

Dietary intake modification is important for the treatment of chronic kidney disease (CKD); however, little is known about the association between dietary intake of antioxidant vitamins and kidney function based on gender difference. We examined the relationship of dietary intake of antioxidant vitamins with decreased kidney function according to gender in Japanese subjects. This population-based, cross-sectional study included 936 Japanese participants with the age of 40 years or older. A validated brief self-administered diet history questionnaire was used to measure dietary intakes of vitamin E and its four isoforms, vitamin A and vitamin C. Decreased kidney function was defined as estimated glomerular filtration rate <60 ml/min/1·73 m2. A total of 498 (53·2 %) of the study participants were women. Mean age was 62·4 ± 11·3 years. Overall, 157 subjects met the criteria of decreased kidney function. In the fully adjusted model, a high vitamin E intake is inversely associated with decreased kidney function in women (odds ratio, 0·886; 95 % confidence interval, 0·786–0·998), whereas vitamin E intake was not associated with decreased kidney function (odds ratio, 0·931; 95 % confidence interval, 0·811–1·069) in men. No significant association between dietary intake of vitamins A and C and decreased kidney function was observed in women and men. Higher dietary intake of vitamin E was inversely associated with decreased kidney function in middle-aged and older women, and the result may provide insight into the more tailored dietary approaches to prevent CKD. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the association between handgrip strength (HGS) and albuminuria in the general population of Japan as per sex and age. This population-based, cross-sectional study enrolled 916 Japanese participants aged ≥40 years. Albuminuria was measured and expressed as the urinary albumin-to-creatinine ratio (UACR). Biochemical, nutritional, and anthropometric profiles as well as HGS were measured using standardised protocols. Four hundred and thirty-two (47%) of the study participants were men, and 484 were women, with respective mean ages of 62 ± 11 years and 63 ± 11 years. HGS, older age, high body mass index, presence of hypertension or diabetes, and a decreased estimated glomerular filtration rate were correlated with the log-transformed UACR in subjects of both sexes. Multivariate linear regression analysis showed that HGS was independently associated with the log UACR in both, men [beta coefficient −0.43; 95% confidence interval (CI) −0.73, −0.13] and women (beta coefficient −0.50; 95% CI −0.90, −0.10) aged ≥65 years; however, a similar association was not observed in younger participants. Low HGS was associated with albuminuria in older men and women in Japan. [ABSTRACT FROM AUTHOR]

Abstract: For multi-scale and multi-modal neural modeling, it is needed to handle multiple neural models described at different levels seamlessly. Database technology will become more important for these studies, specifically for downloading and handling the neural models seamlessly and effortlessly. To date, conventional neuroinformatics databases have solely been designed to archive model files, but the databases should provide a chance for users to validate the models before downloading them. In this paper, we report our on-going project to develop a cloud-based web service for online simulation called “Simulation Platform”. Simulation Platform is a cloud of virtual machines running GNU/Linux. On a virtual machine, various software including developer tools such as compilers and libraries, popular neural simulators such as GENESIS, NEURON and NEST, and scientific software such as Gnuplot, R and Octave, are pre-installed. When a user posts a request, a virtual machine is assigned to the user, and the simulation starts on that machine. The user remotely accesses to the machine through a web browser and carries out the simulation, without the need to install any software but a web browser on the user’s own computer. Therefore, Simulation Platform is expected to eliminate impediments to handle multiple neural models that require multiple software. [Copyright &y& Elsevier]

Abstract: For multi-scale and multi-modal neural modeling, it is needed to handle multiple neural models described at different levels seamlessly. Database technology will become more important for these studies, specifically for downloading and handling the neural models seamlessly and effortlessly. To date, conventional neuroinformatics databases have solely been designed to archive model files, but the databases should provide a chance for users to validate the models before downloading them. In this paper, we report our on-going project to develop a cloud-based web service for online simulation called “Simulation Platform”. Simulation Platform is a cloud of virtual machines running GNU/Linux. On a virtual machine, various software including developer tools such as compilers and libraries, popular neural simulators such as GENESIS, NEURON and NEST, and scientific software such as Gnuplot, R and Octave, are pre-installed. When a user posts a request, a virtual machine is assigned to the user, and the simulation starts on that machine. The user remotely accesses to the machine through a web browser and carries out the simulation, without the need to install any software but a web browser on the user’s own computer. Therefore, Simulation Platform is expected to eliminate impediments to handle multiple neural models that require multiple software. [Copyright &y& Elsevier]

Protein phosphorylation plays critical roles in a variety of intracellular signaling pathways and physiological functions that are controlled by neurotransmitters and neuromodulators in the brain. Dysregulation of these signaling pathways has been implicated in neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder and schizophrenia. While recent advances in mass spectrometry-based proteomics have allowed us to identify approximately 280,000 phosphorylation sites, it remains largely unknown which sites are phosphorylated by which kinases. To overcome this issue, previously, we developed methods for comprehensive screening of the target substrates of given kinases, such as PKA and Rho-kinase, upon stimulation by extracellular signals and identified many candidate substrates for specific kinases and their phosphorylation sites. Here, we developed a novel online database to provide information about the phosphorylation signals identified by our methods, as well as those previously reported in the literature. The "KANPHOS" (Kinase-Associated Neural Phospho-Signaling) database and its web portal were built based on a next-generation XooNIps neuroinformatics tool. To explore the functionality of the KANPHOS database, we obtained phosphoproteomics data for adenosine-A2A-receptor signaling and its downstream MAPK-mediated signaling in the striatum/nucleus accumbens, registered them in KANPHOS, and analyzed the related pathways. [ABSTRACT FROM AUTHOR]

An abstract of the research paper "Simulation Platform: Cloud-Computing Meets Computational Neuroscience," by Yutaka Hirata and colleagues, presented at the Twentieth Annual Computational Neuroscience Meeting, held in Stockholm, Sweden, from July 23-28, 2011.